Preproapelin is a 77 amino acid protein expressed in the human CNS and peripheral tissues, e.g. lung, heart, and mammary gland. Peptides comprising C-terminal fragments of varying size of apelin peptide were shown to activate the G protein-coupled receptor, APJ receptor (Habata, et al., 1999, Biochem Biophys Acta 1452:25-35; Hosoya, et al., 2000, JBC, 275(28):21061-67; Lee, et al., 2000, J Neurochem 74:34-41; Medhurst, et al., 2003, J Neurochem 84:1162-1172). Many studies indicate that apelin peptides and analogues convey cardiovascular actions through their interaction with the APJ receptor (also known as APLNR), such as endothelium-dependent vasodilation (Tatemoto et al., 2001, Regul Pept 99:87-92), positive inotropic actions (Szokodi et al., 2002, Circ Res 91:434-440; Maguire, et al., 2009, Hypertension 54:598-604, epub before print on Jul. 13, 2009) and myocardial regional ischemia and reperfusion (Pisarenko, et al., 2013, J Pharmacol Pharmacother. “Effects of structural analogues of apelin-12 in acute myocardial infarction in rats”, epub before print). Apelin-13, in particular, is a potent inotrope which could provide a treatment for heart failure by increasing heart contractility (Dai, et al., 2006, Eur J Pharmacol 553(1-3): 222-228; Maguire, et al, 2009, Hypertension. 54:598-604).
Transcriptional profiling of pre- and post-surgical ventricle tissue in human patients revealed that APLNR was the most significantly upregulated gene (Chen et al, 2003, Circulation, 108:1432-39). Apelin (apelin−/−) and APJ (APJ−/−) knockout studies in mice suggest that lack of an endogenous apelin-APJ pathway leads to a decreased ability to respond to cardiovascular stress, such as exercise (Charo et al., 2009, Am J Physiol. Heart Circ. Physiol., 297:H1904-1913).
Apelin has also been reported in the regulation of insulin and mechanisms of diabetes and obesity-related disorders. In mouse models of obesity, apelin is released from adipocytes and is directly upregulated by insulin (Boucher, et al., 2005, Endocrinol 146:1764-71). Apelin knockout mice demonstrate diminished insulin sensitivity (Yue, et al., 2010, Am J Physiol Endocrinol Metab 298:E59-E67).
APLNR-modulating agents also find utility in HIV treatment, since synthetic apelin peptides inhibited HIV-1 entry into CD4-APLNR-expressing cells (Cayabyab, M., et al., 2000, J. Virol. 74: 11972-11976). Furthermore, APLNR inhibitors, i.e. capable of blocking pathological angiogenesis, may be useful in inhibiting tumor growth or vascularization in the retina (Kojima, Y. and Quertermous, T., 2008, Arterioscler Thromb Vasc Biol; 28; 1687-1688; Rayalam, S. et al. 2011, Recent Pat Anticancer Drug Discov 6(3):367-72). Apelin neuroprotection is also seen where apelin-13, apelin-17 and apelin-36 act through signaling pathways to promote neuronal survival (Cheng, B, et al., 2012, Peptides 37(1):171-3).
APLNR binding agents are useful in ameliorating cardiovascular disease, as well as cancer, and diabetes, among other apelin related diseases. Since apelin peptides are rapidly cleared from the circulation and have a short plasma half-life of no more than eight minutes (Japp, et al, 2008, J of Amer College Cardiolog, 52(11):908-13), apelin is currently dosed continuously to see a therapeutic effect.
There is a need in the art for improved apelin binding agents as therapeutic agents, particularly those having extended half-life, while maintaining APLNR binding activity.